Palladium(II)-catalyzed direct annulation of 2-chloronicotinaldehyde with 2-bromothiophenol via novel C(formyl)-C(aryl) coupling strategy

Article abstract of DOI:10.1007/s11164-021-04536-1

An efficient and unprecedented method to the synthesis of 1-azathioxanthone derivatives has been developed by means of palladium-catalyzed C(formyl)-C(aryl) coupling followed by SNAr reaction. Optimization study was carried out through different catalyst,

Full text of DOI:10.1007/s11164-021-04536-1

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-021-04536-1
Palladium(II)‑catalyzed direct annulation
of 2‑chloronicotinaldehyde with 2‑bromothiophenol
via novel C(formyl)‑C(aryl) coupling strategy
Mayur I. Morja1 · Prakashsingh M. Chauhan1 · Kishor H. Chikhalia1
Received: 1 March 2021 / Accepted: 5 July 2021
© The Author(s), under exclusive licence to Springer Nature B.V. 2021
Abstract
An efcient and unprecedented method to the synthesis of 1-azathioxanthone deriv-
atives has been developed by means of palladium-catalyzed C(formyl)-C(aryl) cou-
pling followed by SNAr reaction. Optimization study was carried out through dif-
ferent catalyst, ligand, base and solvent. This approach displays various exclusive
characteristics such as operational convenience, moderate to good isolated yields
and decent functional group tolerance.
Graphic Abstract
Keywords 1-Azathioxanthone · Cross dehydrohalogenative coupling (CDC) ·
C(formyl)-C(aryl) coupling · Pd(II) catalyst
*
Kishor H. Chikhalia
chikhalia_kh@yahoo.com
1
Department of Chemistry, Veer Narmad South Gujarat University, Surat, Gujarat 395007, India
Vol.:(0123456789)
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M. I. Morja et al.
Introduction
The C-H bond activation has been remained a focal point of overwhelming study
throughout chronicle of chemical research as it is omnipresent structural motifs
in organic compounds [1–8]. The C-H bond having much higher bond dissocia-
tion energy is typically thought as the inert bond [9–12]. Thus, harsh reaction
condition and multistep procedure is often required for C-H activation process.
Unsurprisingly, reorganization of hydrocarbon by C-H bond activation into target
molecules is inherently difcult task. The most appealing prospect of C-H func-
tionalization logic is the potential to expand retrosynthetic tree by decreasing the
step of reaction in contemporary organic chemistry [13]. Particularly, the direct
functionalization of inert formyl C-H bond is susceptible to introduce functional-
ity in complex organic molecule obviating the necessity of pre-functionalization
with high atom-economy and energy efciency [14, 15]. In last two decades, the
exploitation of convenient as well as environmentally benign process for the crea-
tion of carbon–carbon and carbon-heteroatom (N,O,S) bond via C-H activation
is of capital importance [16–20]. Despite tremendous progress being made, the
rapid and efcient construction of C(formyl)-C(aryl) bond via formyl C-H activa-
tion in the presence of TM-metal catalyst remains a challenging issue. Inspired
from previous eforts, we are prompted to functionalize formyl C-H bond through
transition metal-catalyzed cross dehydrohalogenative coupling (CDC) reaction.
Though we could employ other routes, palladium-catalyzed CDC pathway was
thought as indispensable tool owing to its importance in such type of transforma-
tions [21–26].
As a feedstock and pervasive functional group, aldehyde represents an ideal
starting material for construction of complex organic molecules [27–32]. The
designing of innovative synthetic methodology for the functionalization of alde-
hyde C-H bond is extremely desirable. Nickel-catalyzed arylation of aldehyde has
been successful since the pioneering work of Cheng in 2002 (Scheme 1a). Aryl
halides were well coupled with aldehyde in the presence of Ni(L2)Br2/Zn catalytic
system [33]. In 2010, Martin and co-worker represented the synthesis of benzo-
cyclobutanone via palladium-catalyzed intramolecular acylation of aryl bromide
(Scheme 1b) [34]. Moreover, Suchand and Satyanarayana disclosed Pd(OAc2)/
Ag-catalyzed environmentally benign acylation of iodoarenes with aldehyde
(Scheme 1c) [35]. Liu et al. had reported the role of Ir[dF(CF3)ppy]2(dtbbpy)PF6
and NiCl2 in formyl C-H activation for the synthesis of biarylketone (Scheme 1d)
[36]. Interestingly, MacMillan and co-worker extended the protocol involv-
ing the synergic merger of photo-redox, nickel and hydrogen transfer catalysis
for direct formyl C-H functionalization (Scheme 1e) [37]. Very recently, Wang
et al. developed a nickel/photo-cocatalyzed acylation of aryl halide with aromatic
and aliphatic aldehyde under mild reaction condition (Scheme 1f) [38]. However,
most studies in the feld of aldehyde C-H bond functionalization is focused on
one C–C bond-forming reaction. On the basis of our previous work [39–42] and
also motivated by successful reports on TM-catalyzed transformation from other
researcher [43–48], we envisaged that two bond-forming palladium-catalyzed
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Palladium(II)‑catalyzed direct annulation of…
Scheme 1 Comparision of previous work with this work
C(formyl)-C(aryl) coupling followed by SNAr reaction between 2-chloronicoti-
naldehyde and 2-bromothiophenol may be employed for the synthesis of 1-azathi-
oxanthones (Scheme 1g).
The sulfur-containing heterocycles play signifcant role in the feld of pho-
toelectric material owing to higher resonance energy associated with sulfur atom
than other heteroatom [49, 50]. Particularly, 1-azathioxanthones are efective sen-
sitizers for europium and terbium luminescence [51]. As a consequence, much
efort has been devoted in the development of novel synthetic strategy to generate
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M. I. Morja et al.
substituted 1-azathioxanthones. Up to now, the synthetic approaches mostly relied
on i) Yb(OTf)3/TfOH-catalyzed intramolecular cyclization of phenylthiopyri-
dine acid under solvent free conditions [52], ii) CaF-mediated annulation process
of 3-(trimethylsilyl)pyridin-2-yl trifate with 2-mercaptobenzoate [53], and iii) the
cyclization of (2-fuorophenyl)(2-halophenyl)methanones with N2S.9H2O [54]. In
spite of existing methods, a conceptually general route which utilize easily accessi-
ble starting substrate is still highly demanded. To the best of our knowledge, herein
we report frst palladium-catalyzed synthesis of 1-azathioxanthone derivatives
through aldehyde C-H activation.
Result and discussion
At the outset of our investigation, we carried out an optimization study for the
exemplary reaction utilizing 2-chloronicotinaldehyde and 2-bromothiophenol as
the model substrate. The optimized reaction condition for palladium-catalyzed syn-
thesis of 1-azathioxanthones is shown in Table 1. A series of control experiments
were executed to understand this reaction intensively. Expectedly, when the reac-
tion was performed without a Pd catalyst, no desired conversion was observed
(Table 1, entry 1). It was ascertained that Pd(0) catalysts like Pd2(dba)3 or Pd(PPh3)4
with K2CO3 as base in dimethylformamide (DMF) solvent at 130 °C temperature
under N2 atmosphere aford the hypothesized product in very poor yield (Table 1,
entries 2–3). Much to our delight, when Pd(II) complexes along with ligands were
applied as catalytic system, resultant transformation was achieved in moderate yield
(Table 1, entries 4–6). Among diferent Pd(II) catalysts examined, PdCl2 gave the
best outcome (Table 1, entry 6). Successively, efect of diferent ligands were also
evaluated in the system. L1, L3, L4 and L5 were failed to give improved perfor-
mance when compared with the result of entry no.7 (Table 1, entries 6–10). Here,
we observed that picolinamide ligand were efcient to generate the satisfactory yield
of desired product via formyl C-H functionalization, while other ligand like BINAP
and phenanthroline was inefective in this reaction. The employment of base cesium
carbonate (Cs2CO3) in DMF solvent is found most operative. Other bases such as
Na2CO3, NaHCO3, KOtBu and NaOAc were less efcient or inefcient in driving
this conversion (Table 1, entries 11–15). DMF was the optimal solvent, and the
i
yield was signifcantly lowered when other solvent like PrOH, toluene or dioxane
was used (Table 1, entries 16–18). The same experiment was also carried out under
air atmosphere to check the feasibility of reaction but it results in trace amount of
yield (Table 1, entry 19). Thus, the annulation reaction of 2-chloronicotinaldehyde
with 2-bromothiophenol was conducted using PdCl2 (10 mol%), L2 (20 mol%) and
Cs2CO3 (4 equiv.) in DMF at 130 °C temperature under N2(g) atmosphere for 20 h.
With the optimized reaction condition in hand, the substrate scope with respect to
both coupling partner was discovered. We started to investigate the scope of various
2-chloronicotinaldehyde by using 2-bromothiophenol as coupling partner (Table 2,
1a-1i). Signifcantly, diferent alkyl substituents were well tolerated, providing the
possibility of further derivatization. Here, we could not found noticeable efect of
steric hindrance associated with alkyl group on quantity of yield (Table 2, 1a-1c).
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Palladium(II)‑catalyzed direct annulation of…
Table 1 Optimization of the reaction conditions.a
Entry
Catalyst
Ligand Base
Solvent Yield % b
1
2
3
4
5
6
7
8
–
–
–
–
L1
K2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
–
Pd2(dba)3
Pd(PPh3)4
Pd(OAc)2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Trace
Trace
47%
39%
56%
71%
60%
<10%
<10%
40%
81%
41%
57%
33%
69%
Pd(dppf)Cl2 L1
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
L1
L2
L3
L4
L5
L2
L2
L2
L2
L2
L2
L2
L2
L2
9
10
11
12
13
14
15
c16
17
18
d19
Kk Cs2CO3 DMF
KOtBu
DMF
DMF
DMF
iPrOH
Toluene 38%
Dioxane 29%
NaHCO3
NaOAc
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
<10%
aReaction condition: 1a (0.8 mmol, 1 equiv.), 2a (2.0 mmol, 2.5 equiv.), Pd(II) catalyst (10 mol%), L2
(20 mol%), Cs2CO3 (4 equiv.) in 6.0 ml of solvent for 20 hours at 130oC under N2(g) atmosphere
bIsolated yield
cReaction carried out at 100 °C
dReaction carried out under air atmosphere
Examination under standard condition showed that the substrate with electron releas-
ing substitution on pyridine ring aforded relatively lower yield than those with
electron withdrawing substitution (Table 2, 1d-1i). Notably, in the case of 2-chloro-
1-methyl-1H-pyrrole-3-carbaldehyde and 2-chlorothiophene-3-carbaldehyde, the
coupling-cyclization reaction also worked well, afording the desired products 3j-3 k
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M. I. Morja et al.
Table 2 Substate scope
Entry
1
2
3
Yield
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Palladium(II)‑catalyzed direct annulation of…
Table 2 (continued)
Entry
1
2
3
Yield
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M. I. Morja et al.
Table 2 (continued)
Entry
1
2
3
Yield
in good yields (Table 2, 1j-1 k). We subsequently replaced 2-chloronicotinaldehyde
by 2-chloro3-formylquinoline to highlight the versatility of reaction (Table 2, 1 l-1o).
Interestingly, condensed quinolines were obtained by the treatment of 2-chloro3-for-
mylquinoline with 2-bromothiophenol. Such type of condensed N-heterocycles are
imperative molecules for material science applications. Next we used the optimal
reaction condition in the synthesis of 1-azathioxanthones derivatives by reacting sub-
stituted 2-bromothiophenol with 2-chloronicotinaldehyde (Table 2, 2b-2 h). Substitu-
ents such as alkyl, alkoxy, nitro, trifouroalkyl on 4th position of 2-bromothiophenol
produce the corresponding product in good yield. In short, it was noted that all the
combinations which were screened gave the anticipated product regardless of elec-
tron donating group and electron withdrawing group at R or R’ (Table 2).
On the basis of previous literature [55, 56] and result obtained from experiments, a
plausible mechanistic route is represented in Scheme 2. Initially, PdCl2 was converted
to transient palladium intermediate (Z1) by the coordination with two N donor atom
of L2 ligand in DMF solvent. Then, Z1 underwent ligand exchange with Cs2CO3 to
form intermediate (Z2), releasing cesium-halide. Organopalladium complex (Z3) will
be formed upon the interaction of aryl aldehyde with Z2 via aldehyde C-H activation.
Oxidative addition of Z3 to C–Br bond of 2-bromothophenol generated adduct Z4.
1 3

Palladium(II)‑catalyzed direct annulation of…
Scheme 2 Proposed mechanism
Succeedingly, Z4 experienced reductive elimination to produce Z5 [2-chloropyridin-
3-yl)(2-mercaptophenyl)methanone]. Finally, intramolecular aromatic nucleophilic
substitution of Z5 with Cs2CO3 base aforded the desired product 1-azathioxanthone.
Conclusion
We have revealed strategy of palladium-catalyzed annulation of 2-chloronicoti-
naldehyde with 2-bromothiophenol which provides an efcient protocol for con-
struction of 1-azathioxanthone in good to higher yield under fairly mild reaction
1 3

M. I. Morja et al.
condition. The strategy shows noticeable tolerance of various functional groups that
are attached to both substrates. Further studies on detailed mechanistic insight and
synthesis of valuable advance materials based on the present methodology are in
progress.
Experimental section
General information
2-Chloronicotinaldehydes, 2-bromothiophenols, palladium catalysts, ligands, base
and solvents were purchased commercially and were used as received without
any further purifcation. All reactions were supervised by thin-layer chromatog-
raphy using Merck 60 F254 precoated silica gel plates (0.25 mm thickness). Col-
umn chromatography was performed using 60–120 and 200–400 mess silica from
Spectrochem PVT.LTD., Mumbai, India. The newly synthesized compounds were
1
characterized by H NMR, 13C NMR and elemental analysis. Melting points were
determined using open capillaries on a Veego electronic apparatus VMP-D (Veego
1
Instrument Corporation, Mumbai, India) and are uncorrected. H NMR and 13C
NMR spectra were recorded on a 400 MHz FT NMR, Avance III Bruker model
spectrometer using DMSO-d6 as a solvent, and assigned in parts per million (δ).
1H NMR chemical shifts were given on the δ scale (ppm) and were referenced to
internal TMS. All coupling constants (J values) were denoted in Hertz (Hz). Mul-
tiplicities were reported as follows: s, singlet; d, doublet; t, triplet; q, quartet; quin.,
quintet; m, multiplet. The high-resolution mass spectrum (HRMS) was recorded on
a Bruker Daltonics MicroTof. Elemental analysis (C, H, N) was carried out using a
Heraeus CarloErba 1180 CHN analyzer (Hanau, Germany).
General procedure for the synthesis of 5H‑thiochromeno[2,3‑b]pyridin‑5‑one
A mixture of 2-chloronicotinaldehydes (0.113 g, 0.8 mmol, 1 equiv.), 2-bromothio-
phenols (0.378 g, 2 mmol, 2.5 equiv.), PdCl2 (0.017 g, 0.08 mmol, 10.0 mol%),
L2 (0.029 g, 0.16 mmol, 20 mol%) and cesium carbonate (1.04 g, 3.2 mmol, 4.0
equiv.) were dissolved in DMF (6.0 ml). The reaction mixture was stirred at 130 °C
for 20 h under N2 atmosphere and the progress of reaction was monitored continu-
ously by TLC with ethyl acetate: hexane (3:4) eluent system. After the completion
of reaction, crude was poured into crushed ice and then fltered the reaction mixture.
Afterward, reaction mixture was subjected to solvent extraction by adding 20 ml of
ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4, con-
centrated under reduced pressure and purifed by column chromatography to obtain
anticipated product. Characterization data of compound 3a-3t are mentioned in the
supplementary fle.
Supplementary Information The online version contains supplementary material available at https://doi.
org/10.1007/s11164-021-04536-1.
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Palladium(II)‑catalyzed direct annulation of…
Acknowledgements Authors are thankful to IISER-Pune, and IIT-Bombay for the spectral analysis. The
authors express their gratitude to Head of Chemistry Department Prof. N. B. Patel, Veer Narmad South
Gujarat University, Surat, for providing necessary laboratory facilities.
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